ClinicalTrials How Does it Affect Me? What Do I Need to Know?

1. ClinicalTrials.govHow Does it Affect Me?What Do I Need to Know? Presenter Name and contact Info

2. Be aware that… • Any PowerPoint presentation can only be an introduction to a topic. • This subject is complex – this will point you to many other resources – and our office is happy to assist you further. • PowerPoint bullets are neither the law nor the regulations that apply.

3. Learning Objectives • Explain what ClinicalTrials.gov is and what it can do • Explain why you should register your study • FDAAA • CMS • ICMJE • Voluntary (Recruitment etc.) • Identify who is responsible for registration • Provide practice examples • Explain how registration works at YOUR INSTITUTION • Help Resources (institutional & national)

4. What is ClinicalTrials.gov? Why should I be concerned?

5. http://www.ClinicalTrials.gov

6. Help for Registering Studies on ClinicalTrials.gov • “Submit Studies” http://clinicaltrials.gov/ct2/manage-recs • “For Researchers” http://clinicaltrials.gov/ct2/help/for-researcher • “For Study Record Managers” http://clinicaltrials.gov/ct2/help/for-manager

7. ClinicalTrials.gov can be searched in real time to find enrolling and completed studies including: • Conditions • Interventions • Outcome measures • Sponsors/collaborators • Locations • Phases • Dates (Start and Completion) • Results

8. Rationale • Increase research transparency • Help people find trials To learn more, visit: http://clinicaltrials.gov/ct2/manage-recs/background

9. Evolution of Clinical Trial Disclosure Requirements 1997: FDAMA establishes ClinicalTrials.gov 2000: ClinicalTrials.gov launched 2005: ICMJE requires registration of trials (including at ClinicalTrials.gov) 2007: FDAAA expands ClinicalTrials.gov to require registration of more studies and results and adds penalties for noncompliance 2008: ClinicalTrials.gov addsbasic results modules, including adverse events 2014: MS billing rule implemented requiring NCT # (Full obligatory compliance required as of 1/1/2015) 2014: Notice of Proposed Rulemaking (NRPM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials made available for public comment Adapted from http://clinicaltrials.gov/ct2/about-site/history

10. Recent News • Place holder slide for YOU to insert recent news about ClinicalTrials.gov

11. CMS Updated from D. Zarin, ClinicalTrials.gov, Overview of ClinicalTrials.gov presentation, December 2008, http://prsinfo.clinicaltrials.gov/webinars/module1/resources/Overview_Handouts.pdf.

12. Why should I register a trial in ClinicalTrials.gov?

13. # 1 It’s the law! FDA Amendments Act of 2007 (FDAAA) Most prospective clinical trials involving regulated drugs, biological products, and devices must be registered on ClinicalTrials.gov. (The law also requires reporting of results and adverse events for a subset of these studies.) To learn more about FDAAA 801 Requirements, visit: http://clinicaltrials.gov/ct2/manage-recs/fdaaa

14. It’s the law (a final detail) Some Phase I trials, though they are not Applicable Clinical Trials under FDAAA , are required to register under FDAMA – the earlier law -- which is still in effect. These involve primarily experimental treatments for serious or life-threatening diseases whether using an IND, Group C Cancer drug, or other FDA regulated product. Thus, many studies for cancer and other serious and life-threatening diseases must register regardless of Phase. For more information: http://prsinfo.clinicaltrials.gov/publications/FDLI-Update_2009_508.pdf

15. FDAAA-Registration Required for “Applicable Clinical Trials”: • Interventional studies (drugs, biologics, devices) • Phase 2 – 4 (not phase 1 drug; not small feasibility device;) • US FDA jurisdiction (e.g., IND/IDE or US site) • Studies initiated after September 27, 2007, or initiated on or before that date and were stillongoing as of December 26, 2007 When: • Within 21 days of enrollment of 1st subject • Update at least every 12 months (30 days for Recruitment Status and Primary Completion Date) http://clinicaltrials.gov/ct2/manage-recs/fdaaa

16. FDAAA– Results Submission Required for: • Applicable Clinical Trials • In which the study product is approved (for any use) by FDA When: • Within 12 months of Primary Completion Date (final data collection for primary endpoint) • If product not approved by Primary Completion Date but is approved later, then results due 30 days after approval • Delays are possible, primarily for manufacturer or under limited special circumstances • Pending publication is NOT considered a good cause for delay http://clinicaltrials.gov/ct2/manage-recs/fdaaa

17. #2 Centers for Medicare & Medicaid Services (CMS) Billing Rule • Effective January 1, 2014 - mandatory reporting of the NCT# on claims for items and services provided in “qualified clinical trials” for Medicare coverage. BUT…. If don’t have ability to comply currently, may use the generic # 99999999 until January 1, 2015. After that, you need the NCT#! See http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/SE1344.pdf

18. CMS:What is a “qualifying trial”? * • Purpose of trial must be the evaluation of an item/service that falls within Medicare benefit category (e.g. physicians’ service, durable medical equipment, diagnostic test) • Trial must have therapeutic intent • Trial must enroll patients with diagnosed disease not only healthy volunteers * This slide represents a summary definition. For a complete definition, see 100-03 Medicare NCD at http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=1&ncdver=2&bc=BAABAAAAAAAA&

19. #3 You Want to Publish! • International Committee of Medical Journal Editors (ICMJE) • Requires registration in a publicly available, searchable system. • Scope is broader than FDAAA (i.e., all clinical trials). • Includes 1000+ journals that have adopted the ICMJE policy, such as BMJ, JAMA, and NEJM. • Source:http://www.icmje.org/journals-following-the-icmje-recommendations/

20. ICMJE– Registration:Which studies? Required for Prospective studies that: • Assign subjects to an intervention or concurrent comparison or control groups • Study the cause/effect relationship between medical intervention and a health outcome. ICMJE scope is much broader than the scope ofFDAAA: • Interventions include procedures, behavioral treatments, dietary interventions • Health outcomes include any biomedical or health-related measure obtained in participants, including pharmacokinetic measures and adverse events Source: http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/

21. ICMJE- Registration • When to register: • Prior to enrollment of 1st subject • ICMJE doesn’t require results submission, but does encourage it • ICMJE will not consider results data posted in the tabular format required by ClinicalTrials.gov to be prior publication Source: http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/

22. #4 The Trial is NIHfunded Source: http://grants.nih.gov/ClinicalTrials_fdaaa/index.htm

23. Reasons to Register in Clinicaltrials.gov Increasing Recruitment CMS 2014 FDAAA Results & AE Reporting NIH encouragement 2012 FDAAA and FDAMA Registration ICMJE Registration

25. Who is responsible for registering the trial? FDAAA: The Responsible Party (RP) defined as… The Sponsor (or Sponsor-Investigator) • IND/IDE holder • If no IND/IDE, the industry, academic institution or other organization that initiated the study ICMJEandCMS: Anyone can register, but for ICMJE the author is responsible for ensuring complete registration

26. FDAAA: Designation of Responsible Party RP can be designated by the Sponsor to a PI who • Is responsible for conducting the study • Has access to and control over the data • Has the right to publish the trial results, AND • Has the ability to meet the requirements Example of RP designation • PI initiated study at “Your U” funded by NHLBI • “Your U” is the Sponsor (grant funding recipient) • “Your U” can be the RP or designate the PI as the RP Note: even if not designated as RP, the PI can still enter data into ClinicalTrials.gov

27. Who is the RP? (Let’s practice) Department funded/ PI initiated research NIH funded research/ “Your U” is the grantee institution Pharmaceutical company funded research/ multi-center study including site at “Your U” Device company funded research/ “Your U” PI is the IDE holder Cooperative Group study

28. What happens if I don’t register?

29. Consequences of Noncompliance FDAAA • Public notices of noncomplianceand violations • Withholding of NIH funds • FDA sanctions • Civil monetary penalties (up to $10,000/day) CMS • Billing will be affected: delayed or denied ICMJE • Cannot publish in journals following ICMJE policy, and other select journals

30. What are my responsibilities for the following studies? Hmmm…

31. Study #1 Effectiveness of Bupropion for Treating Nicotine Dependence in Young People • Study Design: Multi-center, Randomized, Efficacy Study • Interventions: Bupropion, Placebo • Primary Outcome: Smoking behavior over 6 months Register? For FDAAA? For ICMJE? Results? Responsible Party?

32. Study #2 Effects of Chronic Sleep Restriction in Young and Older People • Study Design: Open label, Crossover Assignment • Interventions: Chronic sleep restriction • Primary Outcome: Changes in sleep and waking EEG measures, frequent measures of performance, attention, alertness • Other fact: Two universities collaborating, Dr. A @ AU and Dr. B at BU; Dr. B designed study, but A will enroll more Register? For FDAAA? For ICMJE? Results? Responsible Party?

33. Study #3 Assess the impact on Quality of Life (QoL) of long term caregivers of patients with multiple sclerosis. • Centers/sample size: Multi-site, 450 subjects • Intervention/method: Caregivers take QoL survey monthly for 2 years • Other fact: Funded by Pharmaceutical Co. Register? For FDAAA? For ICMJE? Results? Responsible Party?

34. Study #4 Implantable device designed to relieve the symptoms of heart failure through counter-pulsation technology. • Study Design: Open Label • Intervention: Implantable device (IDE obtained) • Primary outcome: to test the feasibility of the device • 8 people enrolled, 6 month study Register? For FDAAA? For ICMJE? Results? Responsible Party?

35. Study #5 Dental graduate student is the investigator for a medical device study. • Study Design: Randomized • Intervention: Treatment with 1 of 3 different FDA approved medical devices • Primary Outcome: Which device increases fluoride in saliva the most? Register? For FDAAA? For ICMJE? Results? Responsible Party? Who will follow up when she graduates?

36. Study #6 – Last one Hip Fracture Study • Method: Compile data from electronic medical record (EMR) over a two year period for 1700 subjects • Data elements: smoking status, use of alcohol, bone marrow density, weight, and height • Primary Outcome: Determine the validity of a new hip fracture risk assessment method compared to FRAX, World Health Organization’s fracture risk tool Register? For FDAAA? For ICMJE? Results? Responsible Party?

37. What is the FDAAA requirement for informed consent language?

38. Informed Consent Language • FDA Mandated Changes in Consent Form Language • The FDA has added a new element of consent that is required for “applicable clinical trials.” All applicable clinical trials are required to include this new element of consent by March 7, 2012. • By federal regulation, the required language must be incorporated verbatim and cannot be altered in any way. “A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time.” • Subjects who were consented before March 7, 2012 will NOT have to be re-consented or otherwise sign addendum consent with this language. For more information or questions, contact the “YOUR U” IRB office or office of regulatory affairs.

39. “As required by law” • Note: you should only include that section if the trial is an “applicable clinical trial” required by law to post in ClinicalTrials.gov. • If not, do not use this language. Guidance for Sponsors, Investigators, and Institutional Review Boards Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c) (Small Entity Compliance Guide) Feb. 2012 Nonbinding on government!

40. Coming Soon … Perhaps • Notice of Public Rulemaking (NPRM) for FDAAA 801 – issued November 2014 • Notable changes from current requirements and practice : • A streamlined approach for determining which trials are subject to the proposed regulations and who is responsible for submitting required information. • Expansion of the set of trials subject to summary results reporting to include trials of unapproved products. • Additional data elements that must be provided. • Clarified procedures for delaying results submission. • More rapid updating of several data elements. • Procedures for timely corrections to any errors discovered by the responsible party or by the Agency as it processes submissions prior to posting. • Draft NIH Policy on Dissemination of NIH-Funded Clinical Trial Information – issued November 2014 • “… all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by NIH, who have committed to NIH that they will comply with NIH policies, are expected to ensure that their NIH-funded clinical trials are registered and summary results, including adverse event information, are submitted to ClinicalTrials.gov in accord with the timelines that will be set forth at ClinicalTrials.gov.” Sources: http://www.nih.gov/news/health/nov2014/od-19.htm; http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html

41. What if I have more questions here or in general?

42. Local Contacts: • Add “YOUR U” contacts here for Clinicaltrials.gov or CMS/Billing help • This might also be a place where you might want to discuss any quick CMS billing- and Clinicaltrials.gov coordination issues, which vary widely by institution, explaining how billing will get the number from the trial team.

43. Additional Resources • General ClinicalTrials.gov information http://clinicaltrials.gov/ct2/about-site • FDAAA related information http://clinicaltrials.gov/ct2/manage-recs/fdaaa • For specific questions or comments register@clinicaltrials.gov. • Office of Extramural Research (OER) http://grants.nih.gov/Clinicaltrials_fdaaa/ • Frequently Asked Questions for NIH Grantees http://grants.nih.gov/Clinicaltrials_fdaaa/faq.htm • Instructions for Authors sections of ICMJE journals all have information regarding clinical trial registration http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html CMS • Mandatory Reporting of NCT# Requirement http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/SE1344.pdf • Qualifying Trial information: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=1&ncdver=2&bc=BAABAAAAAAAA&

44. Acknowledgements This slide set was originally made possible in 2012 by a collaboration of Clinical and Translational Science Award (CTSA) organizations (Mayo Clinic, Partners, University of Michigan Medical School, University of Rochester) and the National Library of Medicine.    In 2014 and 2015, individuals from Mayo Clinic, Partners, University of Michigan Medical School, and Duke updated the slides.